Abstract

Among the evolutionary and developmental constraints on the evolution of very large body sizes is an increased risk of developing cancer because large bodied organisms have more cells that can potentially turn cancerous than small-bodied organisms with fewer cells. This expectation predicts a positive correlation between body size and cancer risk, however, there is no correlation between body size and cancer risk across species; this lack of correlation is often referred to as "Peto's Paradox". Here we show that elephants and their extinct relatives (Proboscideans) resolved Peto's Paradox at least in part through re-functionalizing a leukemia inhibitory factor pseudogene (LIF6) with pro-apoptotic functions. The re-functionalized LIF gene is transcriptionally up-regulated by TP53 in response to DNA damage, and translocates to the mitochondria where it induces apoptosis. Phylogenetic analyses of living and extinct Proboscidean LIF6 genes indicates its TP53 response element evolved coincident with the evolution of large body sizes in the Proboscidean stem-lineage. These results suggest that re-functionalizing of a pro-apoptotic LIF pseudogene may have played a role in the evolution of large body sizes in Proboscideans.

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